Several drugs of abuse, including opiates and barbiturates, are reported to produce changes in the content of histamine in the brain. Histamine, which fulfills most of the criteria for a brain transmitter, may be involved in thermoregulation, hormone release, wakefulness, or drinking behaviro. Methods that accurately measure histamine, and its brain metabolites tele-methylhistamine (t-MH) and methylimidazoleacetic acid (MIAA) have not been available. We have developed a gas chromatographic-mas spectrometric (GC-MS) method to measure t-MH, and will complete the development of methods to measure histamine and MIAA by GC-MS. Brain t-MH may represent neuronally released histamine, and thus be a sensitive indicator of neuronal histamine. We will study the effects of reserpine on brain histamine, t-MH and MIAA to test this hypothesis. Pentobarbital elevates mouse brain histamind, possibly by a neuronal anti-release mechanism. If so, brain histamie metabolite content should be decreased while histamine content in increased. We will study the effects of several doses of pentobarbital on whole and regional histamine and metabolite content to test the prediction. We have preliminary evidence suggesting that morphine increases and decreases mouse brain histamine content after low and high doses, respectively; these changes are reported to vary inversely with locomotor activity. We will study this by determining the brain histamine and metabolite response to morphine and other opiate agonists and antagonists in three strains of mice that exhibit different locomotor responses to morphine. The mechanisms of these drug-induced changes in brain histamine and metabolites will be studied by measuring the actions of these drugs on histidine decarboxylase, histamine methyltrans-ferase, and monoamine oxidase B, the enzymes of histamine synthesis and metabolism in brain, and monoamine oxidase B, the enzymes of histamine synthesis and metabolism in brain. Since opiates are known to release histamine from mast cells, and mast cells are known to exist in some brain regions, these drugs will be studied on histamine and metabolites stored and released from mast cells. The specificity of these responses will be studied using several opiate agonists and antagonists. These studies will increase the understanding of opiate and barbiturate action, and enhance knowledge about histamine in brain.